The present invention relates to the preparation of solutions containing imidazole derivatives and to the use of those solutions in the preparation of microspheres. The imidazole derivative containing microspheres are effective in treating fungal infections, particularly in mammals. The microspheres facilitate the oral administration of relatively large amounts of the imidazole derivative, with increased bioavailability.
Many present systems for delivering active agents to targets are severely limited by biological, chemical, and physical barriers, which are imposed by the environment through which delivery occurs, the environment of the target itself, or the target itself. Delivery is also limited, in many instances, by the chemical nature of the active agent. For example, oral delivery is generally ineffective with active agents that are poorly water-soluble.
The imidazole derivative family of compounds is particularly effective against a broad range of fungal infections such as those caused by Trichophyton rubrum, Tricophyton mentagrophytes, Epidermophyton floccsum, and Candida albicans, but these compounds are either partially water soluble or insoluble in water. For example, the solubility of itraconazole in water is less than 0.00001 g/ml.
Partially because imidazole derivatives are typically insoluble in water, they are difficult to administer orally. Consequently although imidazole derivatives are frequently prescribed for the treatment of fungal infections, they have been available only in topical preparations or in oral formulations with limited bioavailability.
In recent years, fungal infections, such as those caused by Candida albicans in particular have become more prevalent and intractable due to their appearance in immunocompromised patients, such as those infected with Human Immunodeficiency Virus (HIV) or those suffering from Acquired Immunodeficiency Syndrome (AIDS).
For example, U.S. Pat. No. 3,717,655 discloses imidazole derivatives which have antifungal and antibacterial activity. These compounds are almost insoluble in aqueous solutions such as water and are very poorly soluble in polar solvents such as ethanol.
Das et al., U.S. Pat. No. 4,912,124, disclose a solvent system for imidazole derivatives that include mixtures of a polar solvent, a polyhydric alcohol that acts as a solubilizing agent, a nonionic or amphoteric surfactant, and a cosmetic humectant. Solutions containing at least 1 percent by weight of the imidazole derivatives can be formulated using this solvent system. However, these formulations are suitable for external topical use only.
Accordingly, there is a need for orally deliverable forms of imidazole derivative antifungal agents.
The present invention provides solutions comprising:
(a) at least about 2.5 parts by weight, based upon 100 parts by weight of solution, of a solute having the formula
wherein R, R1, and R2 are independently hydrogen or lower alkyl;
R3 is hydrogen, methyl or ethyl;
R4 is hydrogen or methyl
Ar is phenyl, monohalophenyl, dihalophenyl, trihalophenyl, mono(lower alkyl)phenyl, di(lower alkyl)phenyl, lower alkoxyphenyl, or halothienyl;
Ar1 is phenyl, monohalophenyl, dihalophenyl, trihalophenyl, mono(lower alkyl)phenyl, di(lower alkyl)phenyl, lower alkoxyphenyl, or cyanophenyl; and
n is 1 or 2; and
(b) a solubilizing effective amount of a solvent comprising at least one volatile organic acid solvent.
Imidazole derivative microspheres are also provided. These microspheres comprise:
(a) an imidazole derivative active agent having the formula 
xe2x80x83wherein
R, R1, and R2 are independently hydrogen or lower alkyl;
R3 is hydrogen, methyl or ethyl;
R4 is hydrogen or methyl
Ar is phenyl, monohalophenyl, dihalophenyl, trihalophenyl, mono(lower alkyl)phenyl, di(lower alkyl)phenyl, lower alkoxyphenyl, or halothienyl;
Ar1 is phenyl, monohalophenyl, dihalophenyl, trihalophenyl, mono (lower alkyl)phenyl, di(lower alkyl)phenyl, lower alkoxyphenyl, or cyanophenyl; and
n is 1 or 2; and
(b) a microsphere forming carrier selected from the group consisting of
(i) a proteinoid;
(ii) an acylated amino acid, poly amino acid, or a salt thereof;
(iii) an sulfonated amino acid, poly amino acid, or a salt thereof;
(iv) a protein or a salt thereof;
(v) an enteric coating material; or
(vi) any combination thereof.
Also contemplated by the present invention is a method for preparing these microspheres. The method comprises:
(A) nebulizing a solution comprising
(a) an imidazole active agent having the formula 
xe2x80x83wherein
R, R1, and R2 are independently hydrogen or lower alkyl;
R3 is hydrogen, methyl or ethyl;
R4 is hydrogen or methyl
Ar is phenyl, monohalophenyl, dihalophenyl, trihalophenyl, mono(lower alkyl)phenyl, di(lower alkyl)phenyl,. lower alkoxyphenyl, or halothienyl;
Ar1 is phenyl, monohalophenyl, dihalophenyl, trihalophenyl, mono(lower alkyl)phenyl, di(lower alkyl)phenyl, lower alkoxyphenyl, or cyanophenyl; and
n is 1 or 2;
(b) an active agent and carrier solubilizing effective amount of a solvent comprising an aqueous solution of at least one volatile organic solvent; and wherein the volume:volume ratio of acid to water in said carrier solution is at least about 3:7, and
(c) microsphere forming a carrier selected from the group consisting of
(i) a proteinoid;
(ii) an acylated amino acid or poly amino acid or a salt thereof;
(iii) an sulfonated amino acid or poly amino acid or a salt thereof;
(iv) a protein or a salt thereof;
(v) an enteric coating material, or
(vi) any combination thereof; and
(B) decreasing said ratio to less than about 3:7, to yield said microspheres. Alternatively, the active agent and the carrier can be solubilized in separate solutions. The separate solutions can be nebulized together and the acid to water ratio then decreased as above.
Methods for the oral administration of imidazole derivatives are also contemplated wherein the microsphere compositions above are orally administered to an animal in need of this treatment.